Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
With an estimated 230,480 new cases in the year 2011, and 39,520 of them fatal, breast cancer remains the most common malignancy and the second leading cause of cancer-related deaths among women in the U.S. (Jemal et al. (2011) CA Cancer J. Clin., 61:69-90). A combination of markers based on breast cancer pathogenesis has led to the classification of breast cancers into different subtypes that are associated with distinct patient outcomes. Thus, estrogen receptor (ER) and progesterone receptor (PR) positive (ER+/PR+) luminal type of breast cancers are amenable to hormonal therapy and show a substantially better outcome (Sorlie et al. (2001) Proc. Natl. Acad. Sci., 98:10869-10874). In contrast, human epidermal growth factor receptor 2 (HER2)/ErbB2-overexpressing and typically ER/PR-negative luminal breast cancers fail to respond to hormonal therapy and show substantially poorer outcomes compared to ER+/PR+ patients. This subtype of patients, however, selectively benefit from ErbB2-directed targeted therapies such as trastuzumab (Hudis, C. A. (2007) N. Engl. J. Med., 357:39-51).
There is a well-accepted role of the hormonal history of a woman as a determinant of her lifetime risk of developing breast cancer (Colditz, G. A. (1998) J. Natl. Cancer Inst., 90:814-823), a well-established pro-oncogenic role of estrogens in animal models (Korach et al. (2003) J. Steroid Biochem. Mol. Biol., 86:387-391; Mohibi et al. (2011) J. Carcinog., 10:35), and a linkage of environmental estrogens to increased risk of breast and other cancers (Colditz, G. A. (1998) J. Natl. Cancer Inst., 90:814-823). These effects are thought to be mediated predominantly by ERs.
ERs function as ligand-activated transcription factors and known ER targets include genes, such as c-myc, PR, cyclin D1, and TGFα, linked to promotion of cell proliferation and other oncogenic traits such as cell motility and invasion (Petz et al. (2000) Mol. Endocrinol., 14:972-985: Sabbah et al. (1999) Proc. Natl. Acad. Sci., 96:11217-11222; Vyhlidal et al. (2000) J. Mol. Endocrinol., 24:329-338). Similar to other transcriptional activators, the ER-dependent gene transcription requires interaction of ERs with transcriptional co-regulators, such as steroid receptor coactivators (SRCs; Johnson et al. (2011) Nat. Med., 17:660-661; Johnson et al. (2012) Mol. Cell Endocrinol., 348:430-439; Xu et al. (2003) Mol. Endocrinol., 17:1681-1692; Xu et al. (2009) Nat. Rev. Cancer 9:615-630) and co-integrators, such as p300/CBP (Chakravarti et al. (1996) Nature 383:99-103; Kamei et al. (1996) Cell 85:403-414). The importance of transcriptional co-regulators is emphasized by the requirement of SRC-3 in development and estrogenic response of the mammary gland in mice (Xu et al. (2000) Proc. Natl. Acad. Sci., 97:6379-6384; Wang et al. (2000) Proc. Natl. Acad. Sci., 97:13549-13554) and by studies demonstrating that overexpression of SRC-3 in human breast cancer cell lines and patient tumors is associated with resistance to anti-estrogen therapy (Osborne et al. (2003) J. Natl. Cancer Inst., 95:353-361). There is a strong need to understand the role of other effectors of ERs in breast cancer for diagnostic and therapeutic methods.